Method for the production of 2,4,5-trimethylphenyl acetic acid

ABSTRACT

The present invention relates to a novel process for preparing 2,4,5-trimethylphenyl-acetic acid by reacting pseudocumene with dichloroacetyl chloride in a Friedel-Crafts reaction to give 2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone, converting the 2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone to 2,4,5-trimethylmandelic acid using an alkali metal hydroxide and reducing the 2,4,5-trimethylmandelic acid to 2,4,5-tri-methylphenylacetic acid.

The present invention relates to a novel process for preparing2,4,5-trimethylphenylacetic acid.

2,4,5-Trimethylphenylacetic acid is a compound which has already beenknown for some time (for example from: J. prakt. Chem. 80 (1909) 193; J.Amer. Chem. Soc. 58 (1936) 629-35). The preparation may be effected, forexample, by a Willgerodt-Kindler reaction starting from2,4,5-trimethylphenylacetophenone. However, this method results in largeamounts of sulfurous wastes. In addition, highly odorous, volatilesulfur compounds may occur.

A further method starts from 2,4,5-trimethylbenzyl bromide. For example,sodium cyanide is used to prepare the corresponding nitrile which issubsequently hydrolyzed (J. Amer. Chem. Soc. 58 (1936) 629-35; DE-A 19602 524). This nitrile can also be obtained by reacting durene(1,2,4,5-tetramethylbenzene) with cyanogen chloride at above 600° C.(DE-A 2 854 210); however, the high toxicity of cyanogen chloride isdisadvantageous in this context. The 2,4,5-trimethylbenzyl bromiderequired may in turn be prepared by brominating durene withN-bromosuccinimide (see, for example, J. Amer. Chem. Soc. 92 (1970)994-8). However, experience has shown that a disadvantage in thiscontext is that such brominations also lead to polybrominated products,so that complicated purification steps become necessary.

A further possibility which has become known is to start from2,4,5-trimethylbenzyl chloride, and to prepare the nitrile therefrom (J.Amer. Chem. Soc. 58 (1936) 629-35; J. Org. Chem. 33 (1968) 2338-42) andthen hydrolyze it. 2,4,5-Trimethylbenzyl chloride is known and can beprepared by chloromethylating pseudocumene (1,2,4-trimethylbenzene).However, it is to be regarded as extremely unfavorable that thechloromethylation proceeds only with unsatisfactory selectivity.Selectivities of about 75-85% are described (J. Org. Chem. 24 (1959)1823-5; U.S. Pat. No. 3,658,923). In addition, owing to the possibilitythat the highly toxic bischloromethyl ether occurs, thechloromethylation is a method which can only be carried out with hightechnical complexity.

Finally, a further possibility for preparing 2,4,5-trimethylphenylaceticacid is to initially react pseudocumene with glyoxylic acid to give2,4,5-trimethylmandelic acid (Atti Accad., Lettere Arti Palermo, Pt. 124(1965) 19-33) and then to reduce it to 2,4,5-trimethylphenylacetic acid(J. Amer. Chem. Soc. 58 (1936) 629-35). However, the preparation of2,4,5-trimethylmandelic acid by the process specified has thedisadvantage that the 2,4,5-trimethylmandelic acid which has alreadyformed reacts with further pseudocumene under the customary reactionconditions and thus forms considerable proportions of2,2′,4,4′,5,5′-hexamethyldiphenylacetic acid (Atti Accad., Lettere ArtiPalermo, Pt. 124 (1965) 19-33), which of course reduce the yield andmake necessary additional purification steps.

All of the methods which have become known hitherto for preparing2,4,5-trimethyl-phenylacetic acid accordingly have sometimesconsiderable shortcomings and disadvantages which complicate thepreparation of 2,4,5-trimethylphenylacetic acid. Since phenylaceticacids, also including 2,4,5-trimethylphenylacetic acid, are importantprecursors, for example for active ingredients in crop protection (cf.WO 97/36868), there is a need for a technically simple method forpreparing 2,4,5-trimethylphenylacetic acid.

It has now been found that 2,4,5-trimethylphenylacetic acid issurprisingly obtained in a high yield and isomeric purity by initiallyreacting pseudocumene with dichloroacetyl chloride in a Friedel-Craftsreaction to give 2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone, andpreparing 2,4,5-trimethylmandelic acid from it using an alkali metalhydroxide and finally reducing it to 2,4,5-trimethylphenylacetic acid.

The preparation of mandelic acids by reacting dihaloacetophenones withan alkali metal hydroxide is a known method (see, for example: Org.Syntheses 35 (1955) 11-14). Likewise already known is the bromination of2,4,5-trimethylphenylethanone (acetylpseudocumene) and/or2-chloro-1-(2,4,5-trimethylphenyl)ethanone (chloro-acetylpseudocumene)to obtain 2,2-dibromo-1-(2,4,5-trimethylphenyl)ethanone and/or2-bromo-2-chloro-1-(2,4,5-trimethylphenyl)ethanone respectively, and the5 reaction of these with aqueous potassium hydroxide solution to give2,4,5-trimethylmandelic acid (J. Amer. Chem. Soc. 57 (1935) 1562-4).However, this method has the disadvantage of having two stages and beingcomplicated.

Dichlorinated acetophenones can be prepared in a likewise two-stageprocess by Friedel-Crafts acylation of the corresponding aromatic withacetyl chloride and subsequent chlorination.

However, it is more advantageous to react the aromatic in question in aone-stage procedure directly with dichloroacetyl chloride in aFriedel-Crafts acylation to give the dichlorinated acetophenone.

While 2,4,5-trimethylphenylethanone (J. prakt. Chemie <2> 41 (1890) 509;J. Amer. Chem. Soc. 52 (1930) 2959-72) and2-chloro-1-(2,4,5-trimethylphenyl)ethanone (J. Amer. Chem. Soc. 57(1935) 1562) have already been known for some time, the2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone required to prepare2,4,5-trimethylphenylacetic acid by the process according to theinvention has hitherto not been described.

The reaction of pseudocumene with acetyl chloride under Friedel-Craftsconditions affords 2,4,5-trimethylphenylethanone in high selectivity(see comparative example 1). In contrast, the corresponding reactionwith chloroacetyl chloride is distinctly less selective (see Comparativeexample 2).

It could therefore not have been expected from the outset that theFriedel-Crafts reaction of pseudocumene with dichloroacetyl chloridewould afford 2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone insufficiently high isomeric purity.

The process according to the invention may be illustrated by thefollowing scheme:

The present invention accordingly likewise provides the novel compound2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone.

Surprisingly, 2,4,5-trimethylphenylacetic acid can be prepared by theprocess according to the invention in a simpler manner, in betterselectivity and in better yield than by the processes which have becomeknown before.

2,2-Dichloro-1-(2,4,5-trimethylphenyl)ethanone is prepared by the firststep of the process according to the invention by reacting pseudocumenewith dichloroacetyl chloride in the presence of a Friedel-Craftscatalyst.

Useful Friedel-Crafts catalysts in the process according to theinvention may be, for example, aluminum chloride, iron (III) chloride,tin tetrachloride or zeolites. Preference is given to using aluminumchloride as the Friedel-Crafts catalyst.

The amount of Friedel-Crafts catalyst to be used in the processaccording to the invention is not critical. For example, from 0.8 to 1.2mol of catalyst per dichloroacetyl chloride may be used. Preference isgiven to from 0.9 to 1.1 mol of dichloroacetyl chloride per mole ofdichloroacetyl chloride.

Useful solvents for the Friedel-Crafts reaction in the process accordingto the invention are substantially inert solvents, for examplenitrobenzene, carbon disulfide, methylene chloride, 1,2-dichloroethaneor pseudo cumene itself. Preference is given to carbon disulfide,1,2-dichloroethane and pseudo cumene. Particular preference is given topseudocumene.

The amount of dichloroacetyl chloride to be used in the processaccording to the invention is not critical and may vary within widelimits. When a solvent is used, for example, from 0.8 to 1.2 mol ofdichloroacetyl chloride per mole of pseudocumene may be used. Preferenceis given to from 0.9 to 1.1 mol of dichloroacetyl chloride per mole ofpseudocumene.

When an excess of pseudocumene is used as a solvent, the ratio ofdichloroacetyl chloride to pseudocumene will naturally be distinctlysmaller.

The first step of the process according to the invention may be carriedout at temperatures between −20 and +60° C. Preference is given totemperatures between −10 and +30° C.

The reaction times of the first step of the process according to theinvention are between 1 and 24 hours.

The alkali metal hydroxide used in the second step of the processaccording to the invention may be, for example, NaOH, KOH and CSOH.Preference is given to NaOH and KOH; particular preference is given toNaOH.

The amount of alkali metal hydroxide is from 3 to 7 mol per mole of2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone. Preference is given tofrom 4 to 6 mol per mole of2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone.

A useful solvent for the second step of the process according to theinvention is water.

The second step of the process according to the invention may be carriedout at temperatures between −20 and +120° C. Preference is given totemperatures between +20 and +110° C.

The reaction times of the second step of the process according toinvention are between 1 and 24 hours.

The reduction of 2,4,5-trimethylmandelic acid in the third step of theprocess according to the invention may be carried out by various methodsknown in principle for reducing mandelic acids, for example by means ofhydrogen over suitable catalysts, or by means of red phosphorus.Preference is given to carrying out the reduction with red phosphorus.

The reduction with red phosphorus is effected in the presence ofcatalytic amounts of iodide, of a solvent and of a strong acid.

In the third step of the process according to the invention, the redphosphorus is used in amounts of from 0.67 to 3 mol per mole of2,4,5-trimethylmandelic acid. Preference is given to from 1 to 2 mol permole of 2,4,5-trimethylmandelic acid. Excesses of red phosphorus may berecovered and reused.

The iodide source used in the third step of the process according to theinvention may be hydrogen iodide, KI or NaI. In principle, iodine mayalso be used. Preference is given to using NaI or KI.

The amount of iodide is from 1 to 30 mol percent (based on2,4,5-trimethylmandelic acid); preference is given to using from 5 to 20mol percent.

Useful solvents in the third step of the process according to theinvention are formic acid, acetic acid, propionic acid, etc., mixturesof these solvents, or from 70 to 85% aqueous phosphoric acid. Preferenceis given to from 70 to 85% aqueous phosphoric acid and acetic acid;particular preference is given to acetic acid.

The strong acid used in the third step of the process according to theinvention is conc. sulfuric acid, conc. hydrochloric acid or from 80 to85% aqueous phosphoric acid. Preference is given to conc. sulfuric acidand conc. hydrochloric acid. Particular preference is given to conc.hydrochloric acid.

When the solvent used is from 80 to 85% aqueous phosphoric acid, theaddition of a further acid may naturally be dispensed with.

The third step of the process according to the invention may be carriedout at temperatures between +20 and +120° C. Preference is given totemperatures between +60 and +110° C.

The reaction times of the third step of the process according to theinvention are between 1 and 24 hours.

The preparation of 2,4,5-trimethylphenylacetic acid by the processaccording to the invention is to be illustrated by the followingpreparative examples:

PREPARATIVE EXAMPLES Example 12,2-Dichloro-1-(2,4,5-trimethylphenyl)ethanone

At 0-5° C., 146.6 g of AlCl₃ are introduced in portions into a mixtureof 333 g of pseudocumene and 147.7 g of dichloroacetyl chloride within2-3 hours. Afterward, the mixture is stirred at 0-5° C. for a further 2hours and allowed to come to room temperature. The reaction mixture isstirred into 3 300 ml of ice-water containing 66.7 g of conc.hydrochloric acid. Extraction is effected once with 350 ml, and twicewith 500 ml each time, of ethyl acetate. The combined organic phases areextracted first with 165 ml of water and then 85 ml of saturated aqueousNaCl solution, dried and concentrated (up to bath temperature 70° C./1mbar). 236.1 g of oil are obtained which, by GC, contain 85.57% oftarget product (TP)=202.0 g=87.4% of theory. In addition, the followingare present: 2.8% of pseudocumene; 2.6% of tetramethylbenzene; 0.57% ofisomeric TP; 2.27% of isomeric TP; 0.55% of isomeric TP; 0.72% ofisomeric TP; 1.21% of isomeric TP. The sum of isomers of the targetproduct is thus 5.32%; i.e. the ratio of TP to isomers is approx. 94:6.

¹H NMR (400 MHz, CDCl₃): δ=2.29 (s; 6H), 2.48 (s; 3H), 6.71 (s; 1H),7.09 (s; 1H), 7.50 (s; 1H) ppm.

MS: m/e=230 (M⁺ for ³⁵Cl; approx. 2% rel. intensity), 147 (M-CHCl₂,100%), 119 (Me₃Ph; 28%).

Example 2 2,2-Dichloro-1-(2,4,5-trimethylphenyl)ethanone

At 0-5° C., 14.7 g of AlCl₃ are introduced in portions into a solutionof 28.3 g of pseudocumene and 14.8 g of dichloroacetyl chloride in 100ml of carbon disulfide within one hour. The mixture is then stirred at0-5° C. for a further 2 hours, allowed to come to room temperature andstirred for a further 2 hours. 50 ml of 2 N hydrochloric acid are addeddropwise to the reaction mixture. Extraction is effected once with 50 mland twice with 25 ml each time, of ethyl acetate. The combined organicphases are extracted with 50 ml of saturated aqueous NaCl solution,dried and concentrated (bath temperature up to 50° C./1 mbar).

29.51 g of oil are obtained which, by GC, contain 61.49% of targetproduct (TP)=18.1 g=78.3% of theory. In addition, the following arepresent: 28.9% of pseudocumene; 3.2% of tetramethylbenzene; 0.47% ofisomeric TP; 1.58% of isomeric TP; 0.40% of isomeric TP; 0.55% ofisomeric TP; 0.82% of isomeric TP. The sum of isomers of the targetproduct is thus 3.82%; i.e. the ratio of TP to isomers is approx. 94:6.

Example 3 2,2-Dichloro-1-(2,4,5-trimethylphenyl)ethanone

The procedure of example 2 is repeated, with the difference thatoperation is effected in 1,2-dichloroethane as the solvent.

28.87 g of oil are obtained which, by GC, contain 59.15% of targetproduct (TP)=17.1 g=74% of theory. In addition, the following arepresent: 19.4% of pseudocumene; 5.6% of tetramethylbenzene; 0.96% ofisomeric TP; 2.71% of isomeric TP; 0.42% of isomeric TP; 0.52% ofisomeric TP; 0.90% of isomeric TP. The sum of isomers of the targetproduct is thus 5.51%; i.e. the ratio of TP to isomers is approx.91.5:8.5.

Example 4 2,4,5-Trimethylmandelic Acid

222 g of 45% sodium hydroxide solution and 400 ml of water are initiallycharged and heated to reflux. Within approx. 90 minutes, 115.6 g of2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone are added dropwise.Subsequently, the reaction mixture is boiled for a further hour, thenadmixed at 45° C. with 400 ml of water and at room temperature with 400ml of MTBE, the phases are separated, the aqueous phase is extractedonce again with 300 ml of MTBE, and is then acidified with sulfuric acidand the precipitated solid is filtered off with suction. The solid isthen washed three times with 50 ml each time of water and then dried.102.4 g of white solid are obtained which, by GC, contains 91.9% oftarget product=94.1 g=96.9% of theory.

Example 5 2,4,5-Trimethylphenylacetic Acid

A mixture of 69.9 g of 2,4,5-trimethylmandelic acid, 38.3 g of 36%hydrochloric acid, 11.2 g of red phosphorus and 6 g of KI in 270 ml ofglacial acetic acid is heated to 100° C. for 16 hours. Subsequently, themixture is diluted at room temperature with 150 ml of glacial aceticacid. The excess of phosphorus is filtered off with suction and washedthree times with 50 ml of glacial acetic acid. The filtrate is admixedwith 150 ml of water and the acetic acid is substantially removed byrotary evaporation at bath temperature 50° C. 60 mbar. The remainingsuspension is adjusted to pH 1 using 5 ml of 20% sulfuric acid and thesolid is filtered off with suction. The solid is washed three times with180 ml of water each time, and this water becomes the first filtrate.This causes solid to precipitate out once again, which is filtered offwith suction through the already existing filtercake. The filtercake iswashed once more with 100 ml of water and dried to constant weight. Thisresults in 64.46 g of white solid which, by GC, contains 95.8% of targetproduct=61.7 g=96.2% of theory.

COMPARATIVE EXAMPLES Comparative Example 1 2,4,5-Trimethylphenylethanone

At 0-5° C., 14.7 g of AICl₃ are introduced in portions into a mixture of60 g of pseudocumene and 7.85 g of acetyl chloride within 1-2 hours.Afterward, the mixture is stirred at 0-5° C. for another 2 hours andallowed to come to room temperature. The reaction mixture is stirredinto 340 ml of ice-water containing 7 g of conc. hydrochloric acid.Extraction is effected once with 35 ml, and twice with 50 ml each time,of ethyl acetate. The combined organic phases are extracted first with20 ml of water and then with 10 ml of saturated aqueous NaCl solution,dried and concentrated (bath temperature of up to 70° C./1 mbar).

14.44 g of oil are obtained which, by GC, contain 89.82% of targetproduct (TP) 12.97 g=80.0% of theory. In addition, the following arepresent: 2.9% of pseudocumene; 0.5% of tetramethylbenzene; 0.4% ofisomeric TP; 1.28% of isomeric TP; 0.49% of isomeric TP; 0.30% ofisomeric TP; 0.62% of isomeric TP. The sum of isomers of the targetproduct is thus 3.09%; i.e. the ratio of TP to isomers is approx. 97:3.

Comparative Example 2 2-Chloro-1-(2,4,5-trimethylphenyl)ethanone

At 0-5° C., 88 g of AlCl₃ are introduced in portions into a mixture of170 g of pseudocumene and 67.7 g of chloroacetyl chloride within 2-3hours. Afterwards, the mixture is stirred at 0-5° C. for another 2 hoursand allowed to come to room temperature. The reaction mixture is stirredinto 1 000 ml of ice-water containing 20 g of conc. hydrochloric acid.Extraction is effected once with 100 ml, and twice with 75 ml each time,of ethyl acetate. The combined organic phases are extracted first with100 ml of water and then with 50 ml of saturated aqueous NaCl solution,dried and concentrated (bath temperature of up to 70° C./1 mbar). 125.77g of oil are obtained which, by GC, contain 65.2% of target product(TP)=82.0 g=69.5% of theory. In addition, the following are present:6.8% of pseudocumene; 1.8% of tetramethylbenzene; 16.7% of isomeric TP;8.0% of isomeric TP. The sum of isomers of the target product is thus24.7%; i.e. the ratio of TP to isomers is approx. 72.5:27.5.

1-2. (canceled)
 3. A process for preparing 2,4,5-trimethylphenylaceticacid comprising (a) reacting pseudocumene with dichloroacetyl chloridein a Friedel-Crafts reaction to give2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone, (b) converting the2,2-dichloro-1-(2,4,5-trimethylphenyl)ethanone to2,4,5-trimethylmandelic acid using an alkali metal hydroxide, and (c)reducing the 2,4,5-trimethylmandelic acid to form2,4,5-trimethylphenylacetic acid. 4.2,2-Dichloro-1-(2,4,5-trimethylphenyl)ethanone.